ES2238870T3 - AMIDA DERIVATIVES OF ARILPIPERIDINE AND ARIL-1,2,5,6-TETRAHYDROPIRIDINE PRESENTING ACTIVITY IN THE 5HT1A RECEIVER. - Google Patents

Abstract

Compounds of formula (I) wherein R1, R2, R3, R4, X and n are defined in specification, are useful for the treatment of anxiety, depression and related CNS disorders, and other related conditions such as the treatment of alcohol and drug withdrawal, sexual dysfunction and Alzheimer's disease.

Description

Amide derivatives of arylpiperidine and aryl-1,2,5,6-tetrahydropyridine which have activity in the 5HT1A receptor.

Background of the invention

U.S. Patent No. 4,882,432 describes ureas that have high affinities for the recipient 5-HT1A. These compounds, as well as those described in US Patent No. 4,797,489, are useful for the treatment of CNS disorders

Description of the invention

The present invention relates to derivatives arylpiperidine amide and aryl-1,2,5,6-tetrahydro-pyridine which are agonists and antagonists of the receptor subtype 5-HT1A. Due to its high binding affinity to 5HT1A receptor, the compounds of the present invention are useful for the treatment of disorders of the central nervous system (CNS) such as depression, anxiety, anxiety attacks, disorder obsessive-compulsive (OCD), sleep disorders, sexual disorders, alcohol and drug addiction, improvement of cognitive ability, Alzheimer's disease, disease Parkinson's, obesity and migraine.

The compounds of the present invention are represented by the general formula (A),

one

in the that:

R1 is alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl; with the proviso that the link point is a carbon atom;

R2 is hydrogen, alkyl or (CH 2) R 5;

R 3 is hydrogen or alkyl;

X is hydrogen, halogen, perhaloalkyl, hydroxy, alkoxy or perhaloalkoxy;

R 4 is aryl or heteroaryl;

R 5 is alkyl, alkenyl or alkynyl;

n is an integer from 1 to 3; and the line of dots is an optional double bond, or a pharmaceutical salt of the same.

In some preferred embodiments of the present invention R1 is cycloalkyl. In other embodiments Preferred of the present invention X is 4- or 5-fluoro, and more preferably X is 5-fluoro In other preferred embodiments of the present invention R 4 is phenyl or pyridyl.

Alkyl, as used herein memory refers to straight or branched chain alkyl from 1 to 6 carbon atoms In some preferred embodiments alkyl is a linear alkyl chain of 1-5 carbon atoms, and in some embodiments 1-4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl In some preferred embodiments, the alkyl group has 1 to 5 carbon atoms. In some embodiments of the present invention the alkyl group may be substituted with one or more substituents

Alkenyl, as used herein memory refers to straight or branched chain alkyl from 2 to 6 carbon atoms that has at least one double bond carbon-carbon Examples of alkenyl groups They include ethylene and propylene. In some embodiments of the present invention the alkenyl group may be substituted with one or more substituents.

Alkynyl, as used herein memory refers to straight or branched chain alkyl of 2 to 6 carbon atoms that has at least one triple bond carbon-carbon Examples of alkynyl groups they include ethynyl and propynyl. In some embodiments of the present invention the alkynyl group may be substituted with one or more substituents.

Cycloalkyl, as used herein memory refers to a monocyclic alkyl group having 3 to 8 carbons Cycloalkyl groups may be substituted or not. replaced. In some preferred embodiments of the present invention the cycloalkyl group may be substituted with one to Three substituents A preferred cycloalkyl substitution is alkyl of 1 to 4 carbon atoms.

Arilo, as used herein memory refers to a monocyclic or bicyclic aromatic ring which has 6 to 10 carbon atoms. The monocyclic rings have preferably 6 members, and the bicyclic rings have preferably ring structures of 8, 9 or 10 members. The Examples of aryl groups include phenyl and naphthyl. Aryl can be substituted with one to three substituents.

Heteroaryl, as used herein memory, refers to monocyclic or bicyclic aromatic rings 5 to 10 members, who have 1 to 3 heteroatoms selected to from N, O and S. Monocyclic rings preferably have 5 or 6 members, and the bicyclic rings preferably have 8, 9 or 10 member ring structures. The examples of heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl e isoquinolyl Preferred heteroaryl groups include pyridyl, furilo and thienyl. The most preferred heteroaryls include 2-, 3- and 4-pyridyl; 2 and 3-fury, and 2- or 3-thienyl Heteroaryls can also be substituted with one to three substituents.

Halogen, as used herein memory, includes fluorine, chlorine, iodine and bromine.

Suitable substituents include, unless otherwise indicated, halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxy alkyl, carboxy, carbamide, dialkylamino and aryl.

The carbon number refers to the number of carbons in the main carbon chain, and does not include atoms of carbon that are part of substituents such as alkyl or alkoxy substituents.

When the combined terms are used, they apply the definition of each individual part of the combination, unless otherwise indicated. For example, alkylcycloalkyl is a alkyl-cycloalkyl group in which alkyl and Cycloalkyl are as described above.

Salts acceptable from the point of view Pharmaceutical are the salts by acid addition, which can be formed from a compound of the above general formula and an acid pharmaceutically acceptable, such as acid phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluenesulfonic, methanesulfonic and the like.

The compounds of the present invention contain a chiral center, which allows various stereoisomeric forms of compounds, such as racemic mixtures, as well as isomers individual opticians Individual isomers can be prepared directly or by asymmetric or stereospecific synthesis, or by conventional separation of optical isomers from the racemic mixture.

The compounds of formula A and the 4- (halo-2-methoxy-phenyl) piperidines F o 4- (halo-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridines H intermediates of the present invention can be prepared by the experts in organic synthesis following conventional methods. For example, in Scheme I, the exchange metal-halogen of a substituted aryl B halide of appropriate mode with a base, such as butyl lithium, forms a carboanion, and treating the resulting mixture with an N-protected C-4-piperidone gives place to a tertiary alcohol D. An example of a protective group of Nitrogen (R *) of 4-piperidone is benzyl, which can be removed by hydrogenation, to give rise to the amine G. The dehydration of G with an acid, such as sulfuric acid, can provide the 4- (halo-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine H desired. Dehydration of tertiary alcohol D, elimination of the nitrogen protecting group and hydrogenation of the bond double, they can lead to 4- (halo-2-methoxy-phenyl) -piperidine F.

Des-halo intermediaries 4- (2-methoxyphenyl) -piperidine F (X = H) and 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) -pyridine H (X = H) are both known compounds, and can be prepared through the following literature procedures:

Van Wijngaarden Ineke et al , J. Med. Chem ., ( 1988 ), 31 (10), 1934-1940.

Perregaard Jens et al ., J. Med. Chem ., ( 1995 ), 38 (11), 1998-2008.

Modica Maria et al ., J. Med. Chem ., ( 1997 ), 40 (4), 574-585.

Solyom Sandor et al ., Heterocycles , ( 1995 ), 41 (6), 1139-1168.

       \ newpage
    

Scheme I

       \ vskip1.000000 \ baselineskip
    

2

The coupling of 4- (X-2-methoxy-phenyl) -piperidine F or 4- (X-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine H with an N-alkyl-amino acid N -protected (I) in the presence of activation reagents, such as 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (DEAC), 1-hydroxybenzotriazole hydrate (HOBT), 4-methylmorpholine (NMO), form Amide J (Scheme II). The protecting group R is of the urethane type, preferably tert- butoxycarbonyl, which can be removed by the action of an acid. After deprotection, the amide can be reduced to form an M amine with a reducing reagent such as lithium aluminum hydride (LAH) or diborane, and then acylated to give rise to compound A.

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Scheme turns to page next)

       \ newpage
    

Scheme II

       \ vskip1.000000 \ baselineskip
    

3

The following specific examples are included to illustrate the synthesis procedures used for the Preparation of the compounds of formula A. In these examples, all Chemicals and intermediates are available in the market or can be prepared by standard procedures that they appear in the literature or are known by experts in the organic synthesis matter. Several embodiments are described preferred to illustrate the invention.

Example 1 {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -piperidine-1-yl] -ethyl} -methyl-amide of the acid 1-methyl-cyclohexanecarboxylic to) 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine

To a solution of 9.8 ml (24 mmol) of butyl lithium (2.5 M solution in hexane) in ether diethyl (20 ml) under N2 atmosphere at -78 ° C, was added slowly 2-Bromo-5-Fluoroanisole (5.0 g, 24 mmol) in diethyl ether (5 ml). The mixture was left heat up to -50 ° C. At that time, it was added 1-benzyl-4-piperidone (4.62 g, 24.4 mmol) in diethyl ether (3 ml). The resulting mixture stirred at -50 ° C for 30 minutes and then heated to room temperature. The reaction was quenched by adding, drop to drop, a saturated solution of NH 4 Cl. The mixture was transferred then to a separating funnel, the layers separated and the layer Aqueous was extracted three times with EtOAc. The combined organic phase dried with Na2SO4, filtered and concentrated. The rapid chromatography (elution with EtOAc-hexanes, 7: 3) gave rise to 5.27 g (68%) of 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine in the form of yellow oil.

b) 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine

To a solution of 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine (1.01 g, 3.20 mmol) in acetic acid (40 ml) at room temperature, 2 drops of concentrated sulfuric acid were added. The solution resulting was heated to reflux and the mixture was stirred for 2 days. The mixture was cooled to room temperature and diluted with EtOAc (100 ml) and water (100 ml). The solution was made alkaline with 50% NaOH solution until pH = 10. The layers separated and the Organic compounds were washed with brine. Aqueous layers combined, they were extracted three times with EtOAc (50 ml). Layers The combined organics were dried with Na2SO4 and dried concentrated. Rapid chromatography (elution with EtOAc-hexane, 1: 1) gave 0.62 g (65%) of 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine in the form of yellow oil.

C) 1-formyl-4- (5-fluoro-2-methoxy-phenyl) -piperidine

10% palladium on carbon (0.62 g) was added to a methanolic solution (20 ml) of 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine (0.62 g, 2.1 mmol) The solution was purged with N2 for 5 minutes, and then formic acid (2 ml, was added dropwise) 88%), and the resulting mixture was stirred at room temperature for two days. The mixture was filtered through Celite and concentrated, to give rise to 0.44 g (90%) of 1-formyl-4- (5-fluoro-2-methoxy-phenyl) -piperidine in the form of colorless oil.

Elemental analysis of : C 13 H 16 FNO 2 2 0.09 (C 3 H 7 NO)

Calculated : C, 65.81; H, 6.80; N, 5.90

Found : C, 65.36; H, 6.87; N, 6.26

d) 4- (5-fluoro-2-methoxy-phenyl) -piperidine

The raw product of 1-formyl-4- (5-fluoro-2-methoxy-phenyl) -piperidine (0.80 g, 3.4 mmol) was dissolved in HCl (16 ml, 0.5 N) and MeOH (5 ml), and the mixture was refluxed for 16 hours. The mixture is cooled to room temperature and made alkaline with NaOH (2.5 N) and extracted with EtOAc (3 x 25 ml), to give rise to 4- (5-fluoro-2-methoxy-phenyl) -piperidine, which was used directly without further purification.

e) tert -butyl ester (R) acid - {1-benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -2-oxo-ethyl} -methyl- carbamic

The above product of 4- (5-fluoro-2-methoxy-phenyl) -piperidine was dissolved in N, N-dimethylformamide (10 ml) at 0 ° C. To the resulting solution was added 0.70 g (2.5 mmol) of 2- [N-methyl-N- ( tert- butoxycarbonyl) -amino] -3-phenyl-propionic acid in a minimum amount of DMF, followed by DEAC (0.48 g, 2.5 mmol), HOBT (0.41 g, 2.5 mmol) and NMO (0.37 ml, 3.4 mmol), and the mixture was stirred overnight ( the reaction temperature was allowed to rise slowly to room temperature). The reaction mixture was diluted with water (50 ml) and EtOAc (50 ml) and the layers were separated. The aqueous layer was washed with HCl (1 N), saturated NaHCO3, and the combined aqueous layers were extracted three times with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated. Flash chromatography, eluting with a gradient of EtOAc-hexane 1: 4 to EtOAc-hexane 3: 7, gave rise to the tert- butyl ester of (R) - {1-benzyl-2- [4- (5-fluoro-) 2-Methoxy-phenyl) -piperidin-1-yl] -2-oxo-ethyl} -methyl-carbamic acid in the form of yellow oil.

f) Hydrochloride (2R) -1- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -2-methylamino-3-phenyl-propan-1-one

The above product of tert- butyl ester of (R) - {1-benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -2-oxo-ethyl} - methyl-carbamic was dissolved in 4M HCl / dioxane (10 ml) and the resulting solution was refluxed. After stirring overnight, the mixture was cooled to room temperature and the solvent evaporated to give 0.38 g (22% in three steps) of the title product.

g) {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxyphenyl) -piperidin-1-yl] -ethyl} -methyl-amine

To a hydrochloride mixture of (2R) -1- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -2-methylamino-3-phenyl-propan-1-one  (0.38 g, 0.93 mmol) in tetrahydrofuran (20 ml) at 0 ° C in atmosphere of N 2 triethylamine (0.14 ml, 1.0 mmol) was added, followed by the dropwise addition of lithium aluminum hydride (1.9 ml, 1.9 mmol, 1 M solution in THF). After the addition, the bath was removed cooling and the mixture was stirred at room temperature for 2.5 hours The reaction was quenched by slowly adding solution. saturated with NH4Cl, and the mixture was filtered through a Celite pad. The solution was concentrated, to give rise to title compound in the form of yellow oil, which was used without further purification.

h) {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -methyl-amide of the acid 1-methyl-cyclohexanecarboxylic

In N2 atmosphere, a solution of {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -methyl-amine (0.12 g, 0.33 mmol) and triethylamine (0.10 ml, 0.74 mmol) in dichloromethane (10 ml) was cooled to 0 ° C. The solution is added acid chloride 1-methyl-1-cyclohexanecarboxylic (93 mg, 0.58 mmol) in a minimum amount of dichloromethane. The The resulting mixture was stirred at 0 ° C overnight. He Solvent was evaporated and the residue was dissolved in EtOAc (50 ml) and water (50 ml). The layers were separated, the organic compounds were washed with water (2 x 50 ml) and brine, and dried with Na 2 SO 4, filtered and concentrated. Chromatography rapid (elution with EtOAc-hexane 1: 3) resulted in 0.14 g (88% yield) of {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxyphenyl) -piperidin-1-yl] -ethyl} -methylamide of 1-methyl-cyclohexane acid carboxylic. An ethanolic solution of the product was heated slowly to reflux, and 1 equivalent of acid was added fumaric in hot solution of ethyl alcohol, to give rise to the fumarate salt of the title compound as a solid White. m.p. 160-165º.

Elemental analysis of : C 30 H 41 FN 2 O 2 {1.01 C 4 H 4 O 4

Calculated : C, 68.43; H, 7.60; N, 4.69

Found : C, 68.38; H, 7.69; N, 4.33

Example 2 {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydro-4H-pyridin-1-yl] -ethyl} -methyl- amide of the acid 1-methyl-cyclohexanecarboxylic to) 4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine

In a round bottom flask maintained at room temperature 1.95 g (6.18 mmol) of 1-Benzyl-4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine, Dry MeOH (40 ml), and the system was purged with N2 for 5 min. 1.95 g of 10% palladium carbon was added to the solution. The system was purged again with N2 for 5 minutes, and then 2 ml of formic acid (88%) was added. Mix resulting was stirred at room temperature under N2 atmosphere for a day At that time, another 2 ml of acid was added formic (88%). The reaction was continued for 2.5 days. Mix was filtered through Celite and concentrated, to give rise to 4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine (0.95 g, 69% yield) in the form of yellow oil.

b) 4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine

To a solution of 4- (5-fluoro-2-methoxy-phenyl) -4-hydroxypiperidine (0.56 g, 2.5 mmol) in acetic acid (20 ml) at room temperature 2 drops of concentrated sulfuric acid and the solution were added resulting heated to reflux for 2 days. The mixture of reaction was cooled to room temperature and diluted with EtOAc (50 ml) and water (50 ml). The solution was made alkaline with solution. of 50% NaOH until pH = 10, the layers were separated and the layer Organic was washed with brine (25 ml). The combined aqueous layers they were extracted three times with EtOAc (3 x 25 ml), and the layers The combined organics were dried with Na2SO4 and dried concentrated, to give rise to 0.49 g (95% yield) of 4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine in the form of yellow oil.

c) tert - butyl ester (R) acid - {1-benzyl-2- [4- (5-fluoro-2-methoxyphenyl) -1,2,5,6-tetrahydropyridin-1-yl] -2 -oxo-ethyl} -methyl-carbamic

The crude product of 4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine (0.49 g, 2.4 mmol) was dissolved in N, N-dimethylformamide (10 ml) at 0 ° C, and the resulting solution was treated with 2- [N-methyl-N- ( tert- butoxycarbonyl) -amino] -3-phenyl-propionic acid (0.73 g, 2.6 mmol) in a minimum amount of DMF, DEAC (0.50 g, 2.6 mmol), HOBT (0.42 g, 3.1 mmol) and NMO (0.40 ml, 3.6 mmol). The mixture was stirred overnight and diluted with water (50 ml) and EtOAc (5 ml). The layers were separated and the organic layer was washed with HCl (1 N), saturated NaHCO 3, and the combined aqueous washings were extracted three times with EtOAc (3 x 25 ml). The combined organic layers were dried with Na2SO4 and concentrated, to give rise to the tert- butyl ester of (R) - {1-benzyl-2- [4- (5-fluoro-2-) Methoxy-phenyl) -1,2,5,6-tetrahydropyridin-1-yl] -2-oxo-ethyl} -methyl-carbamic acid in the form of yellow oil.

d) Hydrochloride (2R) -1- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridin-1-yl] -2-methylamino-3-phenyl-propan-1-one

The crude product of tert -butyl ester of (R) - {1-benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridin-1-yl] acid -2-oxo-ethyl} -methyl-carbamic was dissolved in 10 ml of 4M HCl / dioxane solution and the resulting mixture was refluxed. After stirring overnight, the mixture was cooled to room temperature and the solvent was evaporated, to give 0.62 g (65% yield for two steps) of the title product.

and) {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,3,6-tetrahydropyridin-1-yl] -ethyl} -methyl-amine

To a hydrochloride mixture of (2R) -1- [4- (5-Fluoro-2-methoxy-phenyl) -1,2,3,6-tetrahydropyridin-1-yl] -2-methylamino-3-phenyl-propan-1-one (0.41 g, 1.0 mmol) in 20 ml of tetrahydrofuran at 0 ° C, in atmosphere of N 2, triethylamine (0.14 ml, 1.0 mmol) was added, followed by the slow addition of 1.9 ml (1.9 mmol) of aluminum hydride and lithium (1 M solution in THF). After the addition, the bath was removed from cooling and the mixture was stirred at room temperature for 2.5 hours The reaction was quenched by slowly adding solution. saturated with NH4Cl, and the mixture was filtered through a Celite pad. The solution was concentrated, to give rise to 0.36 g (100%) of {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridin-1-yl] -ethyl} -methyl-amine in the form of yellow oil, which was used without purification subsequent.

F) {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydro-4H-pyridin-1-yl] -ethyl} -methyl- amide of the acid 1-methyl-cyclohexanecarboxylic

In N2 atmosphere, a solution of {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydropyridine-1-yl] -ethyl} -methyl-amine (0.18 g, 49 mmol) and triethylamine (0.14 ml, 1.0 mmol) in dichloromethane (10 ml) was cooled to 0 ° C. The solution is added acid chloride 1-methyl-1-cyclohexanecarboxylic (0.10 g, 0.59 mmol) in 1 ml of dichloromethane and the resulting mixture stirred at 0 ° C to room temperature (molten ice) for all night. The solvent was evaporated and the residue was dissolved in EtOAc (50 ml) and water (50 ml). The layers separated and the Organic compounds were washed with water (50 ml), brine (25 ml), and dried with Na2SO4, filtered and concentrated. Rapid chromatography (elution with EtOAc-hexane, 1: 4) resulted in 0.13 g (55% yield) of the compound of Title. An ethanolic solution of the product slowly warmed until reflux, and 1 equivalent of fumaric acid in hot solution of ethyl alcohol, to give rise to the salt of fumarate of the title compound as a white solid.

P.f. 146-151 ° C

Elemental analysis of : C_30 H_ {39} FN_ {2} {2} \ cdot1.0C_ {4} H_ {4} {4}

Calculated : C, 68.67; H, 7.29; N, 4.71

Found : C, 67.07; H, 7.08; N, 4.54

Example 3 {1-Benzyl-2- [4- (2-methoxy-phenyl) -3,6-dihydro-2H-pyridin-1-yl] -ethyl} -amide of (R) -cyclohexanecarboxylic acid

To a solution of Boc-D-phenylalanine (2.0 g, 7.54 mmol), DEAC (1.45 g, 7.54 mmol) and HOBT (1.53 g, 11.3 mmol) in DMF (20 ml) at 0 ° C was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.87 8.29 mmol), followed by the addition of NMO (1.4 ml, 12.8 mmol). The mixture was stirred under nitrogen for 16 hours at room temperature, diluted with ethyl acetate (100 ml) and washed with 0.1 N HCl (25 ml), saturated NaHCO 3 (25 ml), NaHCO 3 (25 ml) and brine (25 ml). The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the required product (100% yield), which was stirred in 40 ml of 4.0 M HCl / dioxane overnight and concentrated, to give rise to the hydrochloride salt of the unprotected amine. The Amide was dissolved in THF (50 ml) and reduced at 0 ° C by adding LAH 1.0 M / THF (23 ml). After stirring overnight at temperature ambient, the reaction was quenched by adding saturated solution of NH4Cl, filtered through Celite, dried with Anhydrous Na 2 SO 4, filtered and concentrated, to give rise to the required product. Acid chloride was added cyclohexanecarboxylic acid (0.61 g, 4.13 mmol), drop by drop, at a solution of the amine (1.21 g, 3.75 mmol) and triethylamine (1.1 ml, 7.5 mmol) in dichloromethane (20 ml) at 0 ° C. The mixture was stirred in nitrogen atmosphere overnight at room temperature, concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with H2O (50 ml) and then with brine (25 ml). The phase The organic was dried with anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product. The purification by rapid chromatography (elution with acetate ethyl / hexanes) gave rise to 0.47 g of the free base of the title mentioned above. The fumarate salt was prepared and crystallized, to give 0.28 g of the title compound in pale yellow solid form, m.p. 146-148 ° C.

[α] 25 / D = -11.95 ° (MeOH, 8.4 mg / ml)

Elemental analysis of : C_ {28} H_ {36} N_ {2} {2} \ cdot2.0C_ {4} H_ {4} {4} \ cdot0.5H_ {2}

Calculated : C, 64.18; H, 6.73; N, 4.16

Found : C, 64.06; H, 6.74; N, 4.17

Example 4 {1-Benzyl-2- [4- (2-methoxy-phenyl) -3,6-dihydro-2H-pyridin-1-yl] -ethyl} -amide of the acid (R) -1-methyl-cyclohexanecarboxylic

Acid chloride was added 1-methyl-cyclohexanecarboxylic acid (0.66 g, 4.13 mmol), dropwise, to a solution of the amine (1.21 g, 3.75 mmol, prepared exactly as described in example 3 above) and triethylamine (1.1 ml, 7.5 mmol) in dichloromethane (20 ml) at 0 ° C. The mixture was stirred under nitrogen during the entire overnight at room temperature, concentrated in vacuo, diluted with ethyl acetate (50 ml), washed with H2O (25 ml) and brine. The organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product. The purification by rapid chromatography (elution with acetate ethyl / hexanes) gave rise to 0.36 g of the free base of the title mentioned above. The fumarate salt was prepared and crystallized, to give 0.28 g of the title compound in pale yellow solid form, m.p. 102-104 ° C.

[α] 250 / D = -12.19 ° (MeOH, 7.2 mg / ml)

Elemental analysis of : C_ {29} H_ {38} N2 {O} {2} \ cdot1.0C_ {4} H_ {4} {4} \ cdot1.5H2 {O}

Calculated : C, 67.21; H, 7.69; N, 4.75

Found : C, 66.84; H, 7.25; N, 4.43

Example 5 {1-Benzyl-2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of the acid (R) -1-methyl-cyclohexanecarboxylic

To a solution of Boc-D-phenylalanine (2.0 g, 7.54 mmol), DEAC (1.45 g, 7.54 mmol) and HOBT (1.53 g, 11.3 mmol) in DMF (20 ml) at 0 ° C was added 4- (2-methoxyphenyl) piperidine (1.88 g, 8.29 mmol), followed by the addition of NMO (1.4 ml, 12.8 mmol). Mix stirred under a nitrogen atmosphere overnight to room temperature, diluted with ethyl acetate (50 ml) and washed with 0.1 N HCl (20 ml), saturated NaHCO3 (20 ml), H2O (25 ml) and brine. The organic phase was dried with Na2SO4 anhydrous, filtered and concentrated in vacuo, to give rise to required product (100%), which was stirred in 4.0 M HCl / dioxane (40 ml) overnight and concentrated, to give rise to the salt of free amine hydrochloride. The amide was dissolved in THF (30 ml) and it was reduced by adding 1.0 M LAH / THF (23 ml) at 0 ° C. After stirring for overnight, the reaction was quenched by adding NH4CI saturated, filtered through Celite, dried with Na2SO4 anhydrous, filtered and concentrated, to give rise to the product required. Acid chloride was added 1-methylcyclohexanecarboxylic to a solution of the amine (1.22 g, 3.76 mmol) and triethylamine (1.1 ml, 7.5 mmol) in dichloromethane (20 ml) at 0 ° C. The reaction mixture was stirred in nitrogen atmosphere overnight at room temperature, concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with H2O (2 x 25 ml) and then with brine. The phase The organic was dried with anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product. The purification by rapid chromatography (elution with acetate ethyl / hexanes) gave rise to 1.1 g of the free base of the title. The salt of fumarate was prepared and crystallized, to give 0.81 g of the title compound in the form of a pale yellow solid, m.p. 77-79 ° C.

[α] 250 / D = -10.37 ° (MeOH, 10.0 mg / ml)

Elemental analysis of : C 29 H 40 N 2 O 2 \ Cd2.0 C 4 H 4 O 4

Calculated : C, 65.28; H, 7.11; N, 4.11

Found : C, 65.28; H, 7.35; N, 4.16

Example 6 {1-Benzyl-2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of (R) -cyclohexanecarboxylic acid

Was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.87 g, 8.29 mmol) to a solution of Boc-D-phenylalanine (2.0 g, 7.54 mmol), DEAC (1.45 g, 7.54 mmol) and 1.53 g (11.3 mmol) of HOBT in DMF (20 ml) at 0 ° C, followed by the addition of NMO (1.4 ml, 12.8 mmol). The mixture was stirred under nitrogen atmosphere overnight to room temperature, then diluted with ethyl acetate (50 ml), washed with 0.1 N HCl (15 ml), saturated NaHCO3, H2O and finally brine. The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product (100%), which was stirred in HCl 4.0 M / dioxane (40 ml) overnight and concentrated, to give place the amine hydrochloride salt. The amide dissolved in THF (50 ml) and was reduced for 16 hours at 0 ° C by adding LiAlH4 1.0 M / THF (23 ml). The reaction was quenched by adding solution. saturated with NH4Cl, filtered through Celite, dried with Anhydrous Na 2 SO 4, filtered and concentrated, to give rise to the required product (1.22 g). Acid chloride was added cyclohexanecarboxylic acid (0.61 g, 4.13 mmol) to a solution of (1.22 g, 3.76 mmol) of the crude amine and triethylamine (1.1 ml, 7.5 mmol) in dichloromethane (20 ml) at 0 ° C. The mixture was stirred under an atmosphere of nitrogen overnight at room temperature, then it concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with H2O (2 x 50 ml) and then with brine (50 ml). The phase The organic was dried with anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the required amide. The purification by rapid chromatography (elution with acetate ethyl / hexanes) gave 0.53 g of the free base of the title. The fumarate salt was prepared and crystallized, to give 0.19 g of the title compound in the form of a yellow solid pale, m.p. 103-105 ° C.

[α] 25 / D = -10.50 ° (MEOH, 8.2 mg / ml)

Elemental analysis of : C 28 H 38 {N} {2} O2 {\ cdot1.0C4 {4} H4 {4} \ cdot0.75H2 {O}

Calculated : C, 68.12; H, 7.77; N, 4.96

Found : C, 68.05; H, 7.71; N, 4.94

Example 7 {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-3-ylmethyl-ethyl] -amide of the acid 1-methyl-cyclohexanecarboxylic

Was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.0 g, 4.39 mmol) to a solution of N-Boc-3 '- (3'-pyridyl) -D-alanine (1.17 g, 4.39 mmol), DAEC (0.84 g, 4.39 mmol) and HOBT (0.77 g, 1.3 eq) in DMF (20 ml) at 0 ° C, followed by the addition of NMO (0.7 ml, 1.5 eq). The mixture was stirred under nitrogen during the entire overnight at room temperature, then diluted with ethyl acetate (50 ml), washed with 0.1 N HCl (15 ml), saturated NaHCO3, H2O and finally brine. The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product (100%), which was stirred in HCl 4.0 M / dioxane (40 ml) overnight and concentrated, to give place to the amine hydrochloride salt, from which the free base by treatment with a saturated solution of NaHCO 3. The amide was dissolved in THF (50 ml) and the resulting solution was tried adding, dropwise, BH 3 • THF (10 equivalents), and the mixture was refluxed for 16 hours. After cooling, the reaction was stopped by adding 2N HCl, and after stirring for eight hours the mixture was concentrated in vacuo. The aqueous solution is alkalinized and the product was extracted with EtOAc (3 x 25 ml), the Combined organic products were washed with water (50 ml), brine, separated and dried with anhydrous Na2SO4. The filtration and vacuum concentration resulted in the product required (100% yield). Acid chloride was added 1-methylcyclohexanecarboxylic acid (0.17 g, 1.1 mmol) at a solution of (0.35 g, 1.1 mmol) of the crude amine and triethylamine (0.3 ml, 2.2 mmol) in dichloromethane (5 ml) at 0 ° C. The mixture was stirred. under nitrogen atmosphere overnight at temperature ambient, then concentrated in vacuo, diluted with acetate ethyl (50 ml) and washed with H2O (2 x 50 ml) and then with brine (50 ml). The organic phase was dried with Na2SO4 anhydrous, filtered and concentrated in vacuo, to give rise to Amide required. Purification by rapid chromatography (elution with ethyl acetate / hexanes) gave rise to 0.43 g of the free base of the title. The fumarate salt was prepared and crystallized, to give place 0.29 g of the title compound as a colored solid pale yellow, m.p. 99-101 ° C.

Elemental analysis of : C_ {28} H_ {39} N_ {3} {2} \ cdot1,5C_ {4} H_ {4}

Calculated : C, 65.47; H, 7.27; N, 6.74

Found : C, 65.65; H, 7.70; N, 6.67

Example 8 {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-4-ylmethyl-ethyl} -amide of the acid 1-methyl-cyclohexanecarboxylic

Was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.0 g, 4.39 mmol) to a solution of N-Boc-3 '- (4'-pyridyl) -D-alanine (1.17 g, 4.39 mmol), DAEC (0.84 g, 4.39 mmol), and HOBT (0.77 g, 1.3 eq) in DMF (20 ml) at 0 ° C, followed by the addition of NMO (0.7 ml, 1.5 eq). The mixture was stirred under nitrogen during the entire overnight at room temperature, then diluted with ethyl acetate (50 ml), washed with 0.1 N HCl (15 ml), saturated NaHCO3, H2O and finally with brine. The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product (1.9 g, 100%), which was stirred in 4.0 M HCl / dioxane (40 ml) overnight and concentrated, to give place to the amine hydrochloride salt, from which the free base by treatment with a saturated solution of NaHCO 3. The amide (0.5 g, 1.47 mmol) was dissolved in THF (50 ml) and the solution The resulting was treated by adding, dropwise, BH 3 • THF (10 equivalent) and the mixture was refluxed for 16 hours. After cooling, the reaction was stopped by adding 2N HCl, and, after stirring. for eight hours, the mixture was concentrated in vacuo. The solution Aqueous was made alkaline and the product was extracted with EtOAc (3 x 25 ml), The combined organic products were washed with water (50 ml), brine, separated and dried with anhydrous Na2SO4. The filtration and vacuum concentration resulted in the product required (0.33 g, 70% yield). Acid chloride was added 1-methylcyclohexanecarboxylic acid (0.16 g, 1.0 equivalent) to a solution of the crude amine (0.33 g, 1.0 mmol) and triethylamine (0.3 ml, 2.2 mmol) in dichloromethane (5 ml) at 0 ° C. The mixture was stirred under nitrogen atmosphere overnight to room temperature, then concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with H2O (2 x 50 ml) and then with brine (50 ml). The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the required amide. Purification by chromatography rapid (elution with ethyl acetate / hexanes) resulted in 0.33 g of The free base of the title. The fumarate salt was prepared and crystallized, to give rise to 0.29 g of the title compound in white solid form, m.p. 108-110 ° C.

Elemental analysis of : C_ {28} H_ {39} N_ {3} O2 {\ cdot1,5C_ {H} {4} 4_ \ cdot0.5H_ {2}

Calculated : C, 64.54; H, 7.33; N, 6.64

Found : C, 64.34; H, 7.31; N, 6.43

Example 9 {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-3-ylmethyl-ethyl} -methyl-amide of cyclohexanecarboxylic acid

Was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.0 g, 4.39 mmol) to a solution of N-Boc-3 '- (3'-pyridyl) -D-alanine (1.17 g, 4.39 mmol), DAEC (0.84 g, 4.39 mmol), and HOBT (0.77 g, 1.3 eq) in DMF (20 ml) at 0 ° C, followed by the addition of NMO (0.7 ml, 1.5 eq). The mixture was stirred under nitrogen during the entire overnight at room temperature, then diluted with ethyl acetate (50 ml), washed with 0.1 N HCl (15 ml), saturated NaHCO3, H2O and finally brine. The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product (100%), which was stirred in HCl 4.0 M / dioxane (40 ml) overnight and concentrated, to give place to the amine hydrochloride salt, from which the free base by treatment with a saturated solution of NaHCO 3. A solution of the amine in THF (0.37 g, 1.1 mmol in 10 ml), triethylamine (0.15 ml, 1 equivalent) and the mixed anhydride formed to from acetic anhydride / formic acid (1.1 ml) was stirred at 0 ° C for 48 hours The mixture was concentrated in vacuo, water was added. (25 ml) and the product was extracted with dichloromethane (3 x 25 ml). The Combined organic compounds were washed with water (25 ml), Saturated NaHCO3 and dried with anhydrous sodium sulfate. The filtration and vacuum concentration resulted in the product required (0.32 g, 80% yield). The bis-amide was reduced with BH 3 • THF (10 equivalents) as described in example 8, to give rise to required amine (0.24 g, 88% yield) as a solid White. Cyclohexanecarboxylic acid chloride (0.1 g, 1.0 equivalent) to a solution of the amine (0.24 g, 0.7 mmol) and triethylamine (0.2 ml) in dichloromethane (5 ml) at 0 ° C. The mixture is stirred under nitrogen atmosphere overnight at temperature ambient, then concentrated in vacuo, diluted with acetate ethyl (50 ml) and washed with H2O (2 x 50 ml) and then with brine (50 ml). The organic phase was dried with Na2SO4 anhydrous, filtered and concentrated in vacuo, to give rise to Amide required. Purification by rapid chromatography (elution with ethyl acetate / hexanes) gave 0.31 g of the free base of the title. The hydrochloride salt was prepared and crystallized, to give place 0.21 g of the title compound as a white solid, m.p. 148-150 ° C.

Elemental analysis of : C 28 H 39 N 3 O 2 \ cd2HCl \ 1.5 H 2 O

Calculated : C, 61.19; H, 8.07; N, 7.65

Found : C, 61.18; H, 8.14; N, 7.57

Example 10 {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-4-ylmethyl-ethyl} -methyl-amide of cyclohexanecarboxylic acid

Was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.0 g, 4.39 mmol) to a solution of N-Boc-3 '- (4'-pyridyl) -D-alanine (1.17 g, 4.39 mmol), DAEC (0.84 g, 4.39 mmol), and HOBT (0.77 g, 1.3 eq) in DMF (2 ml) at 0 ° C, followed by the addition of NMO (0.7 ml, 1.5 eq). The mixture was stirred under nitrogen during the entire overnight at room temperature, then diluted with ethyl acetate (50 ml), washed with 0.1 N HCl (15 ml), saturated NaHCO3, H2O and finally brine. The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product (100%), which was stirred in HCl 4.0 M / dioxane (40 ml) overnight and concentrated, to give place to the amine hydrochloride salt, from which the free base by treatment with a saturated solution of NaHCO 3. A solution of the amine in THF (0.5 g, 1.47 mmol in 10 ml), triethylamine (0.2 ml, 1 equivalent) and the mixed anhydride formed to from acetic anhydride / formic acid (1.4 ml) was stirred at 0 ° C for 48 hours The mixture was concentrated in vacuo, water was added. (25 ml) and the product was extracted with dichloromethane (3 x 25 ml). The Combined organic compounds were washed with water (25 ml), Saturated NaHCO3, and dried with anhydrous sodium sulfate. The filtration and vacuum concentration resulted in the product required (0.38 g, 70% yield). The bis-amide was reduced with BH 3 • THF (10 equivalents) as described in example 8, giving rise to required amine (0.24 g, 72% yield) as a solid White. Cyclohexanecarboxylic acid chloride (0.1 g, 1.0 equivalent) to a solution of the amine (0.24 g, 0.7 mmol) and triethylamine (0.2 ml) in dichloromethane (5 ml) at 0 ° C. The mixture is stirred under nitrogen atmosphere overnight at temperature ambient, then concentrated in vacuo, diluted with acetate ethyl (50 ml) and washed with H2O (2 x 50 ml) and then with brine (50 ml). The organic phase was dried with Na2SO4 anhydrous, filtered and concentrated in vacuo, to give rise to Amide required. Purification by rapid chromatography (elution with ethyl acetate / hexanes) resulted in 0.31 g (yield of 96%) of the free base of the title. The hydrochloride salt was prepared and crystallized, to give 0.16 g of the title compound in white solid form, m.p. 158-160 ° C.

Elemental analysis of : C 28 H 39 N 3 O 2 \ cd2HCl \ 1.75H2 O

Calculated : C, 60.69; H, 8.10; N, 7.58

Found : C, 60.69; H, 8.32; N, 7.52

Example 11 {1- (4-methoxybenzyl) -2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of (R) -cyclohexanecarboxylic acid

Was added 1,2,3,6-tetrahydro-4- (2-methoxyphenyl) pyridine (1.87 g, 8.29 mmol) to a solution of Boc-D-Tyr (OMe) (2.2 g, 7.54 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide  (1.45 g, 7.54 mmol) and 1.53 g (11.3 mmol) of 1-hydroxybenzotriazole in DMF (20 ml) at 0 ° C, followed by the addition of 4-methylmorpholine (1.4 ml, 12.8 mmol). The mixture was stirred under nitrogen during the entire overnight at room temperature, then diluted with ethyl acetate (50 ml), washed with 0.1 N HCl (15 ml), saturated NaHCO3, H2O and finally brine. The organic phase was dried with Anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the crude product (100%), which was stirred in HCl 4.0 M / dioxane (40 ml) overnight and concentrated, to give place the amine hydrochloride salt. The amide dissolved in THF (50 ml) and was reduced for 16 hours at 0 ° C by adding LiAlH4 1.0 M / THF (23 ml). The reaction was quenched by adding solution. saturated with NH4Cl, filtered through Celite, dried with Anhydrous Na 2 SO 4, filtered and concentrated, to give rise to the required product (1.3 g). Acid chloride was added cyclohexanecarboxylic acid (0.61 g, 4.13 mmol) to a solution of (1.3 g, 3.76 mmol) of the crude amine and triethylamine (1.1 ml, 7.5 mmol) in dichloromethane (20 ml) at 0 ° C. The mixture was stirred under an atmosphere of nitrogen overnight at room temperature, then it concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with H2O (2 x 50 ml) and then with brine (50 ml). The phase The organic was dried with anhydrous Na2SO4, filtered and concentrated in vacuo, to give rise to the required amide. The purification by rapid chromatography (elution with acetate ethyl / hexanes) gave 0.64 g of the free base of the title. The fumarate salt was prepared and crystallized, to give 0.27 g of the title compound in the form of a yellow solid pale.

Elemental analysis of : C 29 H 40 N 3 O 3 {1.01 C 4 H 4 O 4

Calculated : C, 68.25; H, 7.64; N, 4.82

Found : C, 68.19; H, 7.61; N, 4.84

The compounds of the present invention bind with very high affinity to the 5-HT1A receptor and, for consequently, they are useful for the treatment of disorders of the central nervous system such as depression, anxiety, disorders of sleep, sexual disorders, addiction to alcohol and cocaine, improvement of cognitive ability and related problems, in addition to for the treatment of Alzheimer's disease, Parkinson's, obesity and migraine.

5-HT1A receptor binding assay

High affinity for serotonin receptor 5-HT1A was verified by testing the capacity of the compound to displace the [<3> H] 8-OH-DPAT bound to CHO cells stably transfected with the receptor Human 5-HT1A. CHO cells are grown, stably transfected, in DMEM with thermo-activated FBS at 10% and non-essential amino acids. The cells are collected by scraping the plate, transferred to centrifuge tubes and washed twice by centrifugation (2000 rpm for 10 min, 4 ° C) in buffer (Tris 50 mM pH 7.5). The resulting sediments are divided into parts aliquots and stored at -80 ° C. Rehearsal day defrosts cells on ice and resuspended in buffer. The essay of fixation is carried out on a 96 microtiter plate wells in a total volume of 250 µl. Fixing no specific is determined in the presence of 10 mM 5HT, the concentration ligand end is 1.5 nM. After a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF / B filter previously soaked for 30 minutes in 0.5% PEI. Compounds are initially analyzed in a single test point, to determine the percentage of inhibition at 1, 0.1 and 0.01 mM, and Ki values for compounds are determined assets.

Intrinsic receptor activity assay 5-HT1A

The intrinsic activity of the compounds of the The present invention was determined by analyzing the capacity of the Compounds claimed to counteract the stimulation of cyclic adenosine monophosphate (cAMP) in CHO cells transfected from stable form with the human 5-HT1A receptor.

CHO cells, transfected form were cultured stable, in DMEM with 10% thermo-activated FBS and non-amino acids essential. The cells are seeded at a density of? x10 6 cells per well in a 24-well plate and incubate for 2 days in a CO2 incubator. On the second day, it is replaced the medium per 0.5 ml of treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 µM pargiline) and incubate for 10 minutes at 37 ° C. The wells are treated with Forskolin (final concentration 1 µM), followed immediately by the test compound (0.1 and 1 µM for initial screening) and incubate for another 10 min at 37 ° C. The reaction is terminated by removing the medium and adding 0.5 ml of ice cold test buffer (supplied with the RIA kit). The plates are stored at -20 ° C before evaluating the cAMP formation by an RIA assay. The EC50 values for active test compounds. The compounds that do not demonstrate agonist activities (Emax = 0%) they are also analyzed to detect their ability to counteract the agonist-induced activity. In independent experiments, it pre-incubate 6 concentrations of antagonist for 20 minutes before to add agonist and forskolin. The cells are collected as has previously described. The cAMP kit is obtained from Amersham and the RIA is carried out following the kit instructions; and the IC 50 calculations are performed with GraphPad Prism.

4

Accordingly, the compounds of the present invention have high affinity for the 5HT1A receptor subtype and have intrinsic activity, as evidenced by their ability to counteract the stimulation of cyclic adenosine monophosphate (CAMP). Thus, the compounds of the present invention are useful for the treatment of nervous system disorders central and can be administered to a patient suffering from one or more of such disorders. Treatment, as used in the This report refers to the relief or improvement of symptoms of a particular disorder in a patient. In addition, the compounds of The present invention can be administered as part of a regimen of treatment that includes other agents that act in the system central nervous In some preferred embodiments, the Compounds of the present invention are part of a treatment combined that includes a serotonin reuptake inhibitor. Serotonin reuptake inhibitors useful in treatments combined of the present invention are fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. These agents can administered at the same time, in which case they can be combined in one single pharmaceutical form, or at another time, as compounds of the present invention, still being part of the treatment regimen combined.

The compounds of the present invention can administered alone or together with a pharmaceutical excipient conventional.

Valid solid excipients may include one or more substances that can also act as flavorings, lubricants, solubilizers, dispersants, fillers, sliders, compression additives, binders or tablet disintegrants, or an encapsulating material. In the powders, the excipient is a finely divided solid that is mixed with the finely divided active ingredient. In the tablets, the active substance is mixed with an excipient that it has the necessary compression properties in proportions suitable and compact to acquire the desired shape and size. The powders and tablets preferably contain up to 99% of the active principle. Suitable solid excipients include, by example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low waxes melting point and ion exchange resins.

Liquid excipients may be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs The active substance of the present invention can dissolve or suspend in a liquid excipient, acceptable from the pharmaceutical point of view, such as water, a solvent organic, a mixture of both or acceptable oils or fats from the Pharmaceutical point of view. The liquid excipient may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, dispersants, thickeners, colorants, viscosity regulators, stabilizers or osmoregulators. Suitable examples of excipients liquids for oral and parenteral administration include water (especially when it contains additives such as those mentioned above, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example, glycols) and their derivatives, and oils (for example, coconut oil and fractionated peanut oil). For parenteral administration the excipient may also be a fatty ester such as oleate ethyl and isopropyl myristate. Sterile liquid excipients they are used in compositions in the form of sterile liquid for parenteral administration

The liquid pharmaceutical compositions that are sterile solutions or suspensions can be used, for example, in intramuscular, intraperitoneal or subcutaneous injections. The Sterile solutions can also be administered via intravenous Oral administration may be in the form of liquid or solid composition.

Preferably, the pharmaceutical composition is in unit dosage form, for example, in the form of tablets or capsules In such form, the composition is subdivided into doses. units containing appropriate amounts of the active substance. Unit dosage forms may be packaged compositions, for example, containers with powders, vials, ampoules, syringes preloaded or sachets containing liquids. The dosage form unitary can be, for example, a capsule or tablet, by itself themselves, or it may be the appropriate number of any of said compositions in packaged form.

The therapeutically effective dose to be use in the treatment of a specific psychosis should be determined, subjectively, by the attending physician. The variables involved include psychosis or anxiety disorder specific, and the size, age and response pattern of the patient. He new method of the invention for the treatment of disorders related to the 5-HT1A receptor, or that are affected by it, includes administering to animals homeotherms, including humans, an effective amount of by at least one compound of Formula A and its addition salts not toxic, pharmaceutically acceptable. The Compounds can be administered orally, rectally, parenterally, or topically on the skin and mucous membranes. The usual daily dose is 0.01-1000 mg / kg for oral application, preferably 0.5-500 mg / kg, and 0.1-100 mg / kg for parenteral application, preferably 0.5-50 mg / kg.

Claims (20)

1. Compound presenting the formula 5 in the that: R1 is alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl; provided that the link point is a carbon atom; R2 is hydrogen, alkyl or (CH 2) R 5; R 3 is hydrogen or alkyl; X is hydrogen, halogen, perhaloalkyl, hydroxy, alkoxy or perhaloalkoxy; R 4 is aryl or heteroaryl; R 5 is alkyl, alkenyl or alkynyl; n is an integer from 1 to 3; Y the dotted line is a double bond optional, Y the term alkyl, applied to a group or a part of a group, refers to straight or branched chain alkyl of 1 at 6 carbon atoms, which may be substituted by one or more substituents; the term cycloalkyl, applied to a group or to part of a group, refers to cycloalkyl of 3 to 8 atoms of carbon, which may be substituted or unsubstituted; aryl refers monocyclic aromatic rings or bicyclics that have 6 to 10 carbon atoms, which can be substituted with one to three substituents; the term heteroaryl refers to rings 5 to 10 membered monocyclic or bicyclic aromatics, which have from 1 to 3 heteroatoms selected from O, S and N, which has from one to three substituents; the term alkenyl refers to alkenyl of linear or branched chain of 2 to 6 carbon atoms, which has one or more substituents; the term "alkynyl" refers to alkynyl of linear or branched chain of 2 to 6 carbon atoms, which has one or more substituents; Y the substituents are selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxy alkyl, carboxy, carbamide, dialkylamino and aryl; or a pharmaceutical salt thereof. 2. Compound according to claim 1, wherein R1 is cycloalkyl of 3 to 8 carbon atoms. 3. Compound according to claim 2, wherein said cycloalkyl is substituted with an alkyl of 1 to 4 atoms of carbon. 4. Compound according to any of the claims 1 to 3, wherein X is 4-fluoro-o 5-fluoro-. 5. Compound according to any of the claims 1 to 4, wherein R 4 is phenyl or pyridyl. 6. Compound according to claim 5, wherein R 4 is phenyl, pyrid-3-yl or pyrid-4-yl. 7. Compound according to claim 1, which is one of the following: {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -methyl-amide of the acid 1-methyl-cyclohexanecarboxylic; {(1R) -1-Benzyl-2- [4- (5-fluoro-2-methoxy-phenyl) -1,2,5,6-tetrahydro-4H-pyridin-1-yl] -ethyl} -methyl- acid amide 1-
methyl cyclohexanecarboxylic; {1-Benzyl-2- [4- (2-methoxy-phenyl) -3,6-dihydro-2H-pyridin-1-yl] -ethyl} -amide of (R) -cyclohexanecarboxylic acid; {1-Benzyl-2- [4- (2-methoxy-phenyl) -3,6-dihydro-2H-pyridin-1-yl] -ethyl} -amide of the acid (R) -1-methyl-cyclohexane-carboxylic; {1-Benzyl-2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of the acid (R) -1-methyl-cyclohexanecarboxylic; {1-Benzyl-2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of (R) -cyclohexanecarboxylic acid; {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-3-ylmethyl-ethyl} -amide of the acid 1-methyl-cyclohexanecarboxylic; {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-4-ylmethyl-ethyl} -amide of the acid 1-methyl-cyclohexanecarboxylic; {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-3-ylmethyl-ethyl} -methyl-amide of cyclohexanecarboxylic acid; {(1R) -2- [4- (2-Methoxy-phenyl) -piperidin-1-yl] -1-pyridin-4-ylmethyl-ethyl} -methyl-amide of cyclohexanecarboxylic acid; {1- (4-methoxybenzyl) -2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of (R) -cyclohexanecarboxylic acid; or a pharmaceutical salt thereof. 8. Pharmaceutical composition comprising a compound according to any one of claims 1 to 7, and a pharmaceutically acceptable excipient. 9. Use of a compound of formula (I) according to any of claims 1 to 7 in the preparation of a medication for the treatment of a patient suffering from a central nervous system disorder associated with the subtype of 5-hydroxytryptamine 1A receptor. 10. Use according to claim 9, in the that the disorder is depression, anxiety or anxiety attacks. 11. Use according to claim 9, in the that the disorder is a sleep disorder or a disorder sexual. 12. Use according to claim 9, in the that the disorder is addiction to drugs or alcohol. 13. Use according to claim 9, in the that the disorder is a disorder of cognitive ability. 14. Use according to claim 9, in the that the disorder is a neurodegenerative disease. 15. Use according to claim 14, in the that neurodegenerative disease is Parkinson's disease or Alzheimer's disease. 16. Use according to claim 9, in the That the disorder is migraine. 17. Use according to claim 9, in the That the disorder is obesity. 18. Use according to claim 9, which it also includes the administration of a reuptake inhibitor Serotonin 19. Use according to claim 18, in the that the serotonin reuptake inhibitor is selected from between the group consisting of fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. 20. Procedure for the preparation of a compound according to claim 1, comprising acylating a compound of formula M 6 in which n, X, R2, R3 and R 4 are as defined in claim 1, with a acylating agent containing the group -COR_ {1}, in which R_ {1} is as defined in the claim one.